U.S. patent application number 11/105990 was filed with the patent office on 2005-10-20 for process for preparing pyridazinone compounds.
This patent application is currently assigned to Roche Palo Alto LLC. Invention is credited to Kertesz, Denis John, Martin, Michael, Palmer, Wylie Solang.
Application Number | 20050234236 11/105990 |
Document ID | / |
Family ID | 34963814 |
Filed Date | 2005-10-20 |
United States Patent
Application |
20050234236 |
Kind Code |
A1 |
Kertesz, Denis John ; et
al. |
October 20, 2005 |
Process for preparing pyridazinone compounds
Abstract
The present invention provides a process for the preparation
6-[3-(hetero)aryloxy-2-fluoro-benzyl]-2H-pyridazin-3-one compounds
1 where R2 is an optionally substituted aryl or an optionally
substituted heteroaryl, R.sup.6 is NO.sub.2, NH.sub.2, alkyl,
halogen, or a function group readily derived therefrom and R.sup.4c
is hydrogen or alkyl. There also is provided a process for the 1
preparation of phenylacetic acid compounds 2, wherein R.sup.2 and
R.sup.6 are as defined previously and R.sup.5a is hydrogen or
alkyl, which are useful for the preparation of pyridazinone
compounds.
Inventors: |
Kertesz, Denis John;
(Mountain View, CA) ; Martin, Michael; (San
Francisco, CA) ; Palmer, Wylie Solang; (Mountain
View, CA) |
Correspondence
Address: |
ROCHE PALO ALTO LLC
PATENT LAW DEPT. M/S A2-250
3431 HILLVIEW AVENUE
PALO ALTO
CA
94304
US
|
Assignee: |
Roche Palo Alto LLC
|
Family ID: |
34963814 |
Appl. No.: |
11/105990 |
Filed: |
April 14, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60562650 |
Apr 15, 2004 |
|
|
|
Current U.S.
Class: |
544/239 ;
562/434 |
Current CPC
Class: |
C07D 213/65 20130101;
C07D 237/14 20130101; C07D 403/12 20130101; C07D 209/08 20130101;
C07D 209/32 20130101; C07C 253/30 20130101; C07C 255/54 20130101;
C07D 401/12 20130101; A61P 31/18 20180101; C07C 233/65 20130101;
C07C 253/30 20130101; C07C 255/54 20130101; C07C 235/46 20130101;
A61P 43/00 20180101 |
Class at
Publication: |
544/239 ;
562/434 |
International
Class: |
C07D 237/02; C07C
025/27 |
Claims
We claim:
1. A process for the preparation of a compound according to formula
I 42wherein R.sup.1 is A or B; 43R.sup.2 is an aryl radical or a
heteroaryl radical wherein said heteroaryl is selected from the
group consisting of pyridinyl, pyridine N-oxide, indole, indole
N-oxide, pyrimidinyl, pyrazinyl, quinoline, quinoline N-oxide and
pyrrolyl; and said aryl and said heteroaryl are optionally
substituted with zero to three substituents independently selected
from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkenyl,
C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 sulfonyl,
C.sub.1-6 haloalkoxy, C.sub.1-6 haloalkylthio, hydroxy, halogen,
amino, C.sub.1-6 alkylamino, C.sub.1-6 dialkylamino, aminoacyl,
acyl, C.sub.1-6alkoxycarbonyl, carbamoyl, C.sub.1-6
N-alkylcarbamoyl, C.sub.1-6 N,N-dialkylcarbamoyl, nitro and cyano;
R.sup.4a is in each occurrence is independently hydrogen C.sub.1-6
alkyl, tert-butyl or benzyl; R.sup.4b is hydrogen or
--CO.sub.2R.sup.4a; R.sup.4c is hydrogen or C.sub.1-6 alkyl;
comprising the steps of: (i) contacting an alkali metal
(hetero)aryloxide II with 2,3,4-trifluoronitrobenzene in a first
solvent at temperatures from about -30.degree. C. up to about
40.degree. C. to afford a
3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III; 44(ii)
further contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene
compound III with alkali metal salt of an acetic acid ester IV
wherein R.sup.5 is H, CO.sub.2R.sup.5a or C and R.sup.5a is
independently in each occurrence a straight or branched C.sub.1-6
alkyl, in a second solvent at a temperature of at least about
-20.degree. C. up to about 40.degree. C. to afford a
2-fluoro-3-phenoxyphenylacetic ester V. 45
2. A process according to claim 1 which process further comprises
the step of hydrolyzing V wherein R.sup.5 is CO.sup.2R.sup.5a or C
and contacting the resulting mono- or di-carboxylic acid with acid
to afford VI wherein R.sup.5 is CO.sub.2R.sup.4a or C and R.sup.4a
or R.sup.4c is hydrogen or C.sub.1-6 alkyl. 46
3. A process according to claim 2 which process further comprises
the step of contacting VI with a reducing agent to afford amine
VII. 47
4. A process according to claim 3 which process further comprises
the steps of: (i) contacting VII with a diazotizing amine and (ii)
contacting the resulting diazonium salt VIIa with a cuprous
chloride or cuprous bromide to afford VIII wherein X is chloride or
bromide. 48
5. A process according to claim 3 which process further comprises
the step of contacting VII with a diazotizing agent in the presence
of a tetrafluoroborate salt or tetrafluoroboric acid and heating
said diazonium tetrafluoroborate VIIa (X.sup.-=BF.sub.4.sup.-) to
afford VIII wherein X is fluorine.
6. A process according to claim 4 which process further comprises
contacting VIII wherein X is Br with a dialkylzinc, a palladium
compound and DIBAL-H to afford VIII wherein X is alkyl.
7. A compound according to formula III 49wherein R.sup.2 is as
defined in claim 1.
8. A compound according to formula V wherein R.sup.2, R.sup.4a,
R.sup.4c and R.sup.5 are as defined in claim 1. 50
9. A compound according to formula X. 51
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Ser.
No. 60/562,650 filed Apr. 15, 2004, which is hereby incorporated by
reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for the
preparation of
6-(2-fluoro-3-(hetero)aryl-benzyl)-4-alkyl-2H-pyridazin-3-one (1;
R.sup.4c is alkyl) and
6-(2-fluoro-3-(hetero)aryloxy-benzyl)-2H-pyridazin- -3-one
compounds (1; R.sup.4c is hydrogen) compounds where R.sup.1,
R.sup.2, R.sup.4a, R.sup.4c and R.sup.6 are defined below. The
invention also relates to compounds according to formula 2 wherein
R.sup.1 is CH.sub.2CO.sub.2R.sup.4a,
CH(CO.sub.2R.sup.4a)CO.sub.2R.sup.4a or 3 which are useful for the
preparation of 1. The 2H-pyridazin-3-one compounds 1 inhibit human
immunodeficiency virus (HIV) reverse transcriptase and are useful
for treatment of individuals infected with HIV. 2
BACKGROUND OF THE INVENTION
[0003] Pyridazinones are components of numerous pharmacologically
diverse compounds. Thyroxin analogs have been reported, which
contain, inter alia, the pyridazinone ring, and these analogs were
reported to lower plasma cholesterol without the cardio-stimulatory
effect of thyroxine (A. H. Underwood et al. Nature 1986
324(6096):425-429; P. D. Leeson et al. J. Med Chem 1989
32(2):320-326 and P. D. Leeson et al. EP 0188351).
Oxo-pyridazinylmethyl substituted tyrosines that are selective
antagonists for the haematopoietic phosphatase SH2 domain have been
reported (D. J. Dunnington, WO9624343, WO 9702023 and WO9702024).
WO2001085670 (H. Shiohara et al.) discloses related
pyridazinone-containing malonamide derivatives useful for treating
circulatory diseases. EP 810218 (D. A. Allen et al.) discloses
benzoyl substituted benzyl-pyridazinone compounds which are
cyclooxygenase inhibitors and potential antiinflammatory or
analgesic compounds. U.S. Ser. No. 60/457,144 (J. P. Dunn et al.),
hereby incorporated by reference in its entirety, discloses
pyridazinone compounds useful to inhibit HIV reverse
transcriptase.
[0004] The pyridazinone ring can be introduced into a molecule by
alkylation of a phenyl acetic acid derivative 4
(R=CO.sub.2R.sup.4a) or a phenylacetonitrile 4 (R=CN) with
3,6-dichloropyrazine (5a; M. M. Rodgers and J. P. English, U.S.
Pat. No. 2,371,086). Acid- or based catalyzed hydrolysis of the
ester or nitrile 6 (R=CN or COR.sup.4a) affords the corresponding
carboxylic acid which can be isolated if desired, or subjected to
acid-catalyzed decarboxylation in situ. Hydrolysis of the
chloropyridazine affords the pyridazinone 7. (P. D. Leeson and J.
C. Emmett, J. Chem. Soc. Perkin I 1988 3085; D. A. Allen et al., EP
810218). While this process is often satisfactory with 5a wherein
both chlorine carbon bonds are chemically equivalent, unsymmetrical
dichloropyridazinones such as 5b (R.sup.a=alkyl) produce a mixture
of regioisomers which are often difficult to separate. Alternately,
pyridazinones are formally equivalent to 4-oxo-butenoic acid amides
and an appropriately substituted 4-oxo-butenoic acid derivative can
be converted to pyridazinones by exposure to hydrazine hydrate.
3
[0005] The present process affords a convenient alternate route to
4-alkylpyridazinones 7 (R.sup.a=alkyl) in which the regioisomer
problem created by the alkyl substituent is conveniently resolved
in an early convergent step in the process. The present invention
further affords a convenient route tro
3-(hetero)aryloxy-2-fluoro-phenylacetic acid compounds which are
useful intermediates to prepare HIV reverse transcriptase
inhibitors. Moreover, the present process permits the regiospecific
elaboration of four contiguous aryl carbons.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0006] The phrase "a" or "an" entity as used herein refers to one
or more of that entity; for example, a compound refers to one or
more compounds or at least one compound. As such, the terms "a" (or
"an"), "one or more", and "at least one" can be used
interchangeably herein.
[0007] In general, the nomenclature used in this Application is
based on AUTONOM.TM. v.4.0, a Beilstein Institute computerized
system for the generation of IUPAC systematic nomenclature. If
there is a discrepancy between a depicted structure and a name
given that structure, the depicted structure is to be accorded more
weight. In addition, if the stereochemistry of a structure or a
portion of a structure is not indicated with, for example, bold or
dashed lines, the structure or portion of the structure is to be
interpreted as encompassing all stereoisomers of it.
[0008] The term "alkyl" as used herein denotes an unbranched or
branched chain, saturated, monovalent hydrocarbon residue
containing 1 to 10 carbon atoms. The term "lower alkyl" denotes a
straight or branched chain hydrocarbon residue containing 1 to 6
carbon atoms. "C.sub.1-10 alkyl" as used herein refers to an alkyl
composed of 1 to 10 carbons. Examples of alkyl groups include, but
are not limited to, lower alkyl groups include methyl, ethyl,
propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl,
neopentyl, hexyl, heptyl, and octyl.
[0009] The term "alkenyl" as used herein denotes an unsubstituted
hydrocarbon chain radical having from 2 to 10 carbon atoms having
one or two double bonds. The term "lower alkenyl" denotes an
unsubstituted hydrocarbon chain radical containing 1 to 6 carbon
atoms and having one or two double bonds. "C.sub.2-10 alkenyl" as
used herein refers to an alkenyl composed of 2 to 10 carbons.
Examples are vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl
(crotyl).
[0010] The term "haloalkyl" as used herein denotes a unbranched or
branched chain alkyl group as defined above wherein 1, 2, 3 or more
hydrogen atoms are substituted by a halogen. Examples are
1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl,
trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl,
1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl,
2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl,
2,2-dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl.
[0011] The term "cycloalkyl" as used herein denotes a saturated
carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
"C.sub.3-8 cycloalkyl" as used herein refers to an cycloalkyl
composed of 3 to 8 carbons in the carbocyclic ring.
[0012] The term "alkoxy group" as used herein means an --O-alkyl
group, wherein alkyl is as defined above such as methoxy, ethoxy,
n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy,
pentyloxy, hexyloxy, including their isomers. "Lower alkoxy" as
used herein denotes an alkoxy group with a "lower alkyl" group as
previously defined. "C.sub.1-10 alkoxy" as used herein refers to an
--O-alkyl wherein alkyl is C.sub.1-10.
[0013] The term "alkylthio" or "thioalkyl" means an --S-alkyl
group, wherein alkyl is as defined above such as meththio,
ethylthio, n-propylthio, i-propylthio, n-butylthio, hexylthio,
including their isomers. "Lower alkylthio" or "lower thioalkyl" as
used herein denotes an alkylthio group with a "lower alkyl" group
as previously defined. "C.sub.1-10 alkylthio" as used herein refers
to an --S-alkyl wherein alkyl is C.sub.1-10.
[0014] The terms "alkylsulfinyl" and "arylsulfinyl"as used herein
denotes a group of formula --S(.dbd.O)R wherein R is alkyl or aryl
respectively and alkyl and aryl are as defined herein
[0015] The terms "alkylsulfonyl" and "arylsulfonyl"as used herein
denotes a group of formula --S(.dbd.O).sub.2R wherein R is alkyl or
aryl respectively and alkyl and aryl are as defined herein.
[0016] The term "haloalkoxy" as used herein denotes a
--O-(haloalkyl) group, wherein haloalkyl is as defined herein.
Examples of haloalkoxy groups are difluoromethoxy,
2,2,2-trifluoroethoxy, 3-chloropropyloxy. The term "haloalkylthio"
as used herein denotes a --S-(haloalkyl) group.
[0017] The term "halogen" or "halo" as used herein denotes
fluorine, chlorine, bromine, or iodine.
[0018] The terms "amino", "alkylamino" and "dialkylamino" as used
herein denotes --NH.sub.2, --NHR and --NR.sub.2 respectively and R
is alkyl as defined above. The two alkyl groups attached to a
nitrogen in a dialkyl moiety can be the same or different. The
terms "aminoalkyl", "alkylaminoalkyl" and "dialkylaminoalkyl" as
used herein refer to NH.sub.2(CH.sub.2).sub.n--,
RHN(CH.sub.2).sub.n--, and R.sub.2N(CH.sub.2).sub.n-- respectively
wherein n is 1 to 6 and R is alkyl as defined above. "C.sub.1-10
alkylamino" as used herein refers to an-aminoalkyl wherein alkyl is
C.sub.1-10.
[0019] The term "acylamino" as used herein denotes a group of
formula --NHC(.dbd.O)R wherein R is hydrogen, lower alkyl as
defined herein.
[0020] The term "acyl" as used herein denotes a group of formula
--C(.dbd.O)R wherein R is hydrogen or lower alkyl as defined
herein. The term or "alkylcarbonyl" as used herein denotes a group
of formula C(.dbd.O)R wherein R is alkyl as defined herein. The
term "arylcarbonyl" as used herein means a group of formula
C(.dbd.O)R wherein R is an aryl group; the term "benzoyl" as used
herein an "arylcarbonyl" group wherein R is phenyl.
[0021] The terms "alkoxycarbonyl" and "aryloxycarbonyl"as used
herein denotes a group of formula --C(.dbd.O)OR wherein R is alkyl
or aryl respectively and alkyl and aryl are as defined herein.
[0022] The prefix "carbamoyl" as used herein denotes the radical
--CONH.sub.2. The prefix "N-alkylcabamoyl" and
"N,N-dialkylcarbamoyl" means a the radical CONHR' or CONR'R"
respectively wherein the R' and R" groups are independently alkyl
as defined herein. The prefix N-arylcabamoyl" denotes the radical
CONHR' wherein R' is an aryl radical as defined herein.
[0023] The term "polar aprotic solvent" means organic solvents such
as formamide, N,N-dimethylformamide, dimethylsulfoxide,
N-methylpyrrolidone or hexamthylphosphoramide.
[0024] The term "ethereal solvent" means solvents such as
tetrahydofuran, dimethoxyethane, dioxane, and dialkyl ethers such
as diethyl ether and methyl isobutyl ether.
[0025] The term "aryl" as used herein denotes a monovalent aromatic
carbocyclic radical containing 5 to 15 carbon atoms consisting of
one individual ring, or one or more fused rings in which at least
one ring is aromatic in nature, which can optionally be substituted
with one or more, preferably one or three substituents
independently selected from hydroxy, thio, cyano, alkyl, alkoxy,
lower haloalkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl,
nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyl,
alkylaminoalkyl, and dialkylaminoalkyl, alkylsulfonyl,
arylsulfinyl, alkylaminosulfonyl, arylaminosulfonyl,
alkylsulfonylamino, arylsulfonylamino, carbamoyl, alkylcarbamoyl
and dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino,
arylcarbonylamino, unless otherwise indicated. Alternatively two
adjacent atoms of the aryl ring may be substituted with a
methylenedioxy or ethylenedioxy group. Examples of aryl radicals
include, but are not limited to, phenyl, naphthyl, indanyl,
anthraquinolyl tetrahydronaphthyl, 3,4-methylenedioxyphenyl,
1,2,3,4-tetrahydroquinolin-7-yl,
1,2,3,4-tetrahydroisoquinoline-7-yl, and the like. The term
"(hetero)aryl" is used to indicate that the ring substituent can be
either an aryl or a heteroaryl ring.
[0026] The term "aryloxy" as used herein denotes a O-aryl group,
wherein aryl is as defined above. An aryloxy group can be
unsubstituted or substituted with one or two suitable substituents.
The term "phenoxy" refers to an aryloxy group wherein the aryl
moiety is a phenyl ring. The term "heteroaryloxy" as used herein
means an --O-heteroaryl group, wherein heteroaryl is as defined
below. The term "(hetero)aryloxy" is use to indicate the moiety is
either an aryloxy or heteroaryloxy group.
[0027] The term "heteroaryl" or "heteroaromatic" as used herein
means a monocyclic or bicyclic radical of 5 to 12 ring atoms having
at least one aromatic ring containing four to eight atoms per ring,
incorporating one or more N, O, or S heteroatoms, the remaining
ring atoms being carbon, with the understanding that the attachment
point of the heteroaryl radical will be on an aromatic ring. As
well known to those skilled in the art, heteroaryl rings have less
aromatic character than their all-carbon counter parts. Thus, for
the purposes of the invention, a heteroaryl group need only have
some degree of aromatic character. Examples of heteroaryl moieties
include monocyclic aromatic heterocycles having 5 to 6 ring atoms
and 1 to 3 heteroatoms include, but is not limited to, pyridinyl,
pyridazinone, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl,
imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline,
thiadiazole and oxadiaxoline which can optionally be substituted
with one or more, preferably one or two substituents selected from
hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio,
halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino,
alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and
dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl,
alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino
and arylcarbonylamino. Examples of bicyclic moieties include, but
are not limited to, quinolinyl, isoquinolinyl, benzofuryl,
benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and
benzisothiazole. Bicyclic moieties can be optionally substituted on
either ring. The term (hetero)aryl is used to indicate that the
ring substituent can be either an aryl or a heteroaryl ring.
[0028] As used herein, the term "treating", "contacting" or
"reacting" when referring to a chemical reaction means to add or
mix two or more reagents under appropriate conditions to produce
the indicated and/or the desired product. It should be appreciated
that the reaction which produces the indicated and/or the desired
product may not necessarily result directly from the combination of
two reagents which were initially added, i.e., there may be one or
more intermediates which are produced in the mixture which
ultimately leads to the formation of the indicated and/or the
desired product.
[0029] The term "optional" or "optionally" as used herein means
that the subsequently described event or circumstance may but need
not occur, and that the description includes instances where the
event or circumstance occurs and instances in which it does not.
For example, "aryl group optionally mono- or di-substituted with an
alkyl group" means that the alkyl may but need not be present, and
the description includes situations where the aryl group is mono-
or disubstituted with an alkyl group and situations where the aryl
group is not substituted with the alkyl group.
[0030] The term "alkali metal" refers to a group I metal including,
but not limited to lithium (Li.sup.+), sodium (Na.sup.+) or
potassium (K.sup.+). One skilled in the art will be aware that
while these alkali metals are commonly used, other cations such as
magnesium (Mg.sup.2+) may be used without departing from the spirit
of the invention.
[0031] Abbreviations used in this application include: acetyl (Ac),
acetic acid (HOAc), azo-bis-isobutyrylnitrile (AIBN),
1-N-hydroxybenzotriazole (HOBT), atmospheres (Atm), high pressure
liquid chromatography (HPLC), 9-borabicyclo[3.3.1]nonane (9-BBN or
BBN), methyl (Me), tert-butoxycarbonyl (Boc), acetonitrile (MeCN),
di-tert-butyl pyrocarbonate or boc anhydride (BOC.sub.20),
1-(3-dimethylaminopropyl)-3-- ethylcarbodiimide hydrochloride
(EDCI), benzyl (Bn), m-chloroperbenzoic acid (MCPBA), butyl (Bu),
methanol (MeOH), benzyloxycarbonyl (cbz or Z), melting point (mp),
carbonyl diimidazole (CDI), MeSO.sub.2-- (mesyl or Ms),
1,4-diazabicyclo[2.2.2]octane (DABCO), mass spectrum (ms)
diethylaminosulfur trifluoride (DAST), methyl t-butyl ether (MTBE),
dibenzylideneacetone (Dba), N-carboxyanhydride (NCA),
1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-bromosuccinimide (NBS),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylpyrrolidone
(NMP), 1,2-dichloroethane (DCE), pyridinium chlorochromate (PCC),
N,N'-dicyclohexylcarbodiimide (DCC), pyridinium dichromate (PDC),
dichloromethane (DCM), propyl (Pr), diethyl azodicarboxylate
(DEAD), phenyl (Ph), di-iso-propylazodicarboxylate, DIAD, pounds
per square inch (psi), diethyl iso-propylamine (DEIPA), pyridine
(pyr), di-iso-butylaluminumhydride, DIBAL-H, room temperature, rt
or RT, N,N-dimethyl acetamide (DMA), tert-butyldimethylsilyl or
t-BuMe.sub.2Si, (TBDMS), 4-N,N-dimethylaminopyridine (DMAP),
triethylamine (Et.sub.3N or TEA), N,N-dimethylformamide (DMF),
triflate or CF.sub.3SO.sub.2-- (Tf), dimethyl sulfoxide (DMSO),
trifluoroacetic acid (TFA), 1,1'-bis-(diphenylphosphino)ethane
(dppe), 2,2,6,6-tetramethylheptane-2,6- -dione (TMHD),
1,1'-bis-(diphenylphosphino)ferrocene (dppf), thin layer
chromatography (TLC), ethyl acetate (EtOAc), tetrahydrofuran (THF),
diethyl ether (Et.sub.2O), trimethylsilyl or Me.sub.3Si (TMS),
ethyl (Et), p-toluenesulfonic acid monohydrate (TsOH or pTsOH),
lithium hexamethyl disilazane (LiHMDS),
4-Me-C.sub.6H.sub.4SO.sub.2-- or tosyl (Ts), iso-propyl (i-Pr),
N-urethane-N-carboxyanhydride (UNCA), ethanol (EtOH). Conventional
nomenclature including the prefixes normal (n), iso (i-), secondary
(sec-), tertiary (tert-) and neo have their customary meaning when
used with an alkyl moiety. (J. Rigaudy and D. P. Klesney,
Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press,
Oxford.).
Embodiments of the Invention
[0032] The present invention affords a process for the preparation
of 6-(2-fluoro-3-(hetero)aryloxy-benzyl)-4-alkyl-2H-pyridazin-3-one
compounds (8: R.sup.4c=alkyl) and
6-(2-fluoro-3-(hetero)aryloxy-benzyl)-2- H-pyridazin-3-one
compounds (8 R.sup.4c=hydrogen) compounds, wherein R.sup.1 and
R.sup.2 are as defined in claim 1, and said compounds are chemical
intermediates useful for the preparation of said pyridazinones. The
process exploits the lability of fluorine atoms in
trifluoronitrobenzene and results in the regiospecific displacement
of two of the three fluorine atoms resulting by the phenoxy moiety
and the alkylpyridazinone moiety while retaining a fluorine atom
and a nitro group as in 8 (X=NO.sub.2). The nitro group can be
further reduced to an amine which is further utilized to introduce
halogen, alkyl or other substituents into the 4-position. The
conversion of an aromatic amine substituent into a variety of other
functional groups is well known, e.g., Cl, Br or F, and the
preparation of other pyridazinone compounds with other substituents
at the 4-position is within the scope of the present invention. A
halogen, particularly a bromo or chloro substituent can be
converted into the corresponding 4-alkyl substitution by a
dialkylzinc in the presence of a palladium catalyst. 4
[0033] Fluoronitroaromatic compounds are known to be unusually
sensitive to nucleophilic attack by soft nucleophiles. Fluorine
substituents are generally significantly more labile than other
halogen substituents. While hard nucleophiles like water and
hydroxide fail to displace fluoride, soft nucleophiles like
phenols, imidazoles, amines, thiols and some amides facilely
displace fluorine at room temperature (D. Boger et al., Biorg. Med.
Chem. Lett. 2000 10: 1471-75; F. Terrier Nucleophilic Aromatic
Displacement: The Influence of the Nitro Group VCH Publishers, New
York, N.Y. 1991).
[0034] The reaction of sodium methoxide with
2,3,4-trifluoronitrobenzene in methanol has been reported to afford
an inseparable mixture of the corresponding 2- and 4-monomethoxy
and 2,4-dimethoxy derivatives (P. M. O'Neill et al., J. Med. Chem.
1994 37:1362-70). Displacement of the ortho-fluorine of
2,4-difluoronitrobenzenei by amine nucleophiles also has been
reported. (W. C. Lunmma, Jr. et al., J. Med. Chem. 1981
24:93-101).
[0035] The reaction of 2,3,4-trifluoronitrobenzene (Aldrich catalog
No. 33,836-2) with 3-chloro-5-cyanophenol resulted in regiospecific
displacement of the 2-fluoro moiety to afford 9. One skilled in the
art will immediately appreciate that although the process is
exemplified with 3-chloro-5-cyanophenol, a large number of
substituted phenols or hydroxyl substituted heteroaromatic
compounds are readily available and could be used to afford many
other anti-HIV-compounds.
[0036] The displacement reaction can be run in a variety of organic
solvents including, but not limited to, ethers (e.g. diethyl ether,
THF, DME and dioxane) and alcohols (e.g., iso-propanol and
sec-butanol). Solvents capable of directly reacting with the
fluoronitrobenzene are clearly precluded as are solvents which may
result in the loss of regiochemical control. Thus secondary and
tertiary alcohols are acceptable solvents but primary alcohols can
displace fluoride. The skilled chemist would be capable of
identifying acceptable solvents with minimal experimentation. The
phenol is treated with base to afford the phenolate salt. Any
alkali metal salt can be employed in the present process but the
reaction is conveniently carried out with the lithium, sodium or
potassium salts. Sodium phenolates are readily available by
treating the phenol with sodium tert-butoxide or sodium
tert-amylate in tert-butanol or tert-amyl alcohol respectively. The
sodium alcoholate can be prepared by treating the alcohol with
sodium metal or sodium hydride. Potassium phenolates can be
prepared analogously. Alternatively the phenol can be combined with
the sodium alcoholate in THF to afford the salt. The reaction can
be run from about -30.degree. C. to about 40.degree. C. without
significant loss of the regioselectivity. Typically the reactants
are combined at low temperature and allowed to warm to RT after an
initial mixing. Under these conditions the aromatic nucleophilic
displacement proceeds with high regioselectivity at the 2-position
of the substrate 5
[0037] Introduction of the carbon substituent at the 4-position of
the benzene ring was achieved by a second subsequent regioselective
aromatic nucleophilic displacement with a carbon nucleophile.
Suitable carbon nucleophiles are obtained by deprotonation of a
carboxylic acid derivative or a malonic acid diester. Deprotonation
of a carboxylic acid ester or a nitrile is accomplished with
lithium or sodium amide bases such as lithium diisopropylamide,
lithium hexamethyldisilazane, lithium diethylamide. Deprotonation
also can be effected with sodium or potassium alkoxides or with
potassium or sodium hydrides. The deprotonation is generally
accomplished in ethereal solvents or polar aprotic solvents at
temperatures from about -70.degree. C. to about 0.degree. C. Direct
introduction of the pyridazinone is achieved by reacting 9 with
(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl
ester (10). Advantageously, condensation of 9 and 10
regiospecifically affords the 4-methyl compound and tedious
separation of the 4-alkyl and 5-alkylpyridazinone isomers is
avoided.
[0038] The skilled artisan will comprehend that while use of
(hetero)arylacetic acid compounds, such as 10, is sometimes
advantageous, the introduction of the (hetero)aryl moiety can also
be achieved by a multistep process employing malonic acid diesters.
Alkylation of dialkyl malonates, and variations such as mixed
diesters, are a fundamental process in organic synthesis and a
multitude of variations applicable to the present process have been
described (H. O. House, Modern Synthetic Reactions, 2 ed., W. A.
Benjamin, 1972, New York N.Y., pp. 492-570 and 586-595; W.
Carruthers, Some Modern Methods of Organic Synthesis, 3.sup.rd ed.,
Cambridge University Press, Cambridge, UK, 1986, pp. 1-26). For
example, ethyl tert-butyl malonate (12), reacts efficiently 6
[0039] with 9 to afford 13. The resulting
3-(phenoxyphenyl)-substituted malonate 13 can be further
substituted by a second deprotonation and alkylation or converted
to a corresponding phenylacetate (14: R=H) by hydrolysis and
decarboxylation. The resulting phenylacetate can, for example, be
condensed with 3,6-dichloropyrazine to afford unsubstituted
6-chloropyridazines (15a) which can be converted to the
corresponding pyridazinone (15b) by sequential acid hydrolysis and
decarboxylation. Considerable flexibility is possible in the
sequence of steps and all variations are considered to be within
the scope of the invention.
[0040] Thus, in one embodiment of the present invention there is
provided a process for the preparation 7
[0041] of a compound according to formula I wherein R' is A or B;
R.sup.2 is an aryl radical or a heteroaryl radical wherein said
heteroaryl is selected from the group consisting of pyridinyl,
pyridine N-oxide, indole, indole N-oxide, pyrimidinyl, pyrazinyl,
quinoline, quinoline N-oxide and pyrrolyl; and, said aryl radical
and said heteroaryl radical are optionally substituted with zero to
three substituents independently selected from the group consisting
of C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6 haloalkyl,
C.sub.3-8 cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfinyl, C.sub.1-6 sulfonyl, C.sub.1-6 haloalkoxy,
C.sub.1-6 haloalkylthio, hydroxy, halogen, amino, C.sub.1-6
alkylamino, C.sub.1-6 dialkylamino, aminoacyl, acyl, C.sub.1-6
alkoxycarbonyl, carbamoyl, C.sub.1-6 N-alkylcarbamoyl, C.sub.1-6
N,N-dialkylcarbamoyl, nitro and cyano; R.sup.4a is hydrogen
C.sub.1-6 alkyl, tert-butyl or benzyl; R.sup.4b is hydrogen or
--CO.sub.2R.sup.4a and, R.sup.4c is hydrogen or C.sub.1-6 alkyl
comprising the steps of: (i) contacting an alkali metal
(hetero)aryloxide H with 2,3,4-trifluoronitrobenzene in a first
solvent at temperatures from about -30.degree. C. up to about
40.degree. C. to afford a
3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III; 8
[0042] (ii) further contacting said
3,4-difluoro-2-(hetero)aryloxynitroben- zene compound III with
alkali metal salt of an acetic acid ester IV wherein R.sup.5 is
CO.sub.2R.sup.5a or C and R.sup.5a is independently in each
occurence straight or branched C.sub.1-6 alkyl, in second solvent
at a temperature of at least about -78.degree. C. up to about
40.degree. C. to afford a 2-fluoro-3-phenoxyphenylacetic ester
V.
[0043] Suitable first solvents include, but are not limited to
ethereal solvents and secondary and tertiary alcohols. The choice
of a suitable base and second solvent will be influenced by the
reactants. The second solvent is typically an polar aprotic solvent
or an ethereal solvent when strong bases, e.g. alkali metal amides.
Aprotic ether solvents may also be used when sodium or potassium
alkoxides are used as the base. Alkali metal hydrides are typically
used in polar aprotic solvents. The skilled chemist will readily
identify suitable combinations of bases and solvents
[0044] In another embodiment of the present invention there is
provided a process for the preparation of a compound according to
formula V wherein R.sup.2 is 3,5-bis-tert-butylcarbamoyl-phenyl or
3-chloro-5-cyanophenyl which process comprises (i) contacting an
sodium 3,5-bis-tert-butylcarbam- oyl-phenolate or sodium
3-chloro-5-cyano-phenolate with 2,3,4-trifluoronitrobenzene in a
first solvent at temperatures from about -30.degree. C. up to about
40.degree. C. to afford a
3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene or
3,4-difluoro-2-(3-chloro-5-cyano-phenoxy)nitrobenzene wwhich is
further reacted with IV as described below.
[0045] In another embodiment of the present invention there is
provided a process for the preparation of a compound according to
formula III wherein R.sup.2 is 3,5-dicyano-phenyl which process
further comprises (i) contacting sodium
3,5-bis-tert-butylcarbamoyl-phenolate with
2,3,4-trifluoronitrobenzene in an appropriate solvent at
temperatures from about -30.degree. C. up to about 40.degree. C. to
afford a
3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene;
and (ii) contacting
3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitro- benzene
with phosphorus oxychloride or a similar dehydrating agent to
afford 3,4-difluoro-2-(3,5-dicyano-phenoxy)nitrobenzene III
(R.sup.2=3,5-dicyanophenyl). The ether can be convert to IV
(R.sup.2=3,5-dicyanophenyl) as described below.
[0046] In another embodiment of the present invention there is
provided a process for the preparation of a compound according to
formula VI which process comprises the steps of (i) contacting an
alkali metal (hetero)aryloxide II with 2,3,4-trifluoronitrobenzene
in a first solvent at temperatures from about -30.degree. C. up to
about 40.degree. C. to afford a
3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III; (ii)
contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound
III with alkali metal salt of an acetic acid ester IV wherein
R.sup.5 is CO.sub.2R.sup.5a or C and R.sup.5a is independently in
each occurence straight or branched C.sub.1-6 alkyl, in a second
solvent with a base at a temperature of at least about -78.degree.
C. up to about 40.degree. C. to afford a
2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono-
or di-ester and contacting the resulting mono- or di-acid with acid
to afford VI wherein R.sup.5 is CO.sub.2R.sup.4a or C and R.sup.4a
or R.sup.4c is hydrogen or C.sub.1-6 alkyl; and, R.sup.1, R.sup.2
and R.sup.4b are as defined in claim 1. 9
[0047] Replacement of the nitro group with other substituents can
be achieved by a two-step process comprising reduction of the nitro
compound VI to the corresponding amine VII. Reduction of a nitro
group to an amine is well known and can be accomplished with
inorganic reducing agents, e.g. iron, zinc and tin salts in acidic
solvents, or by catalytic hydrogenation. Other conditions which can
be employed in the reduction of aromatic nitro groups include
AlH.sub.3--AlCl.sub.3, hydrazine, TiCl.sub.3, Al--NiCl.sub.2-THF,
formic acid and sulfides such as NaHS, (NH.sub.4).sub.2S or
polysulfides. Aromatic nitro compounds have been reduced to amines
by NaBH.sub.4 in the presence of transition metal catalysts such as
NiCl.sub.2 or CoCl.sub.2. (J. March, Advanced Organic Chemistry J.
Wiley & Sons, New York, 1992 p 1216-1217).
[0048] Aryl chlorides and bromides can be prepared form the
corresponding diazonium salt by treating the diazonium salt with
cuprous chloride or cuprous bromide (the Sandmeyer Reaction). Aryl
diazonium salts are prepared by treating the amine dissolved in
dilute mineral acids and cooled to about 0.degree. to about
10.degree. C. with aqueous sodium nitrite. Less reactive weakly
basic amines require concentrated acids, e.g. con H.sub.2SO.sub.4,
or mixtures of con H.sub.2SO.sub.4 and glacial acetic acid or
phosphoric acid. Fluoroboric acid has also proven useful. An
alternate process can be carried out in an organic solvent, e.g.,
glacial HOAc, MeOH, EtOH, HCONH.sub.2, DMF, acetone and others,
using nitrite esters, e.g., butyl- or pentyl-nitrite. Other
nitrosating agents which can be emploed in non-protic solvents
include nitrosyl chloride, nitrosyl tetrafluoroborate and the like
(K. Schank Synthetic Applications of Diazonium Ions in The
Chemistry of the Diazonium and Diazo Group, S. Patai (ed), Part 2,
1978 John Wiley & Sons, New York, N.Y., pp. 647-648.). Aryl
chlorides and bromides are formed efficiently by treating the aryl
diazonium salt with CuCl or CuBr. A variant of the Sandmeyer
procedure uses metallic copper in the presence of hydrochloric or
hydrobromic acid (the Gatterman reaction). One-step alternatives
two the two step diazotization/Sandmeyer sequence include treating
the amine with t-butyl nitrite and cuprous chloride or bromide at
elevated temperatures (M. P. Doyle et al. J. Org. Chem. 1977
42:2426) or with t-butyl thionitrate and the cuprous halides at
room temperature (S. Oae et al. Bull. Chem. Soc. Japan 1980
53:1065). Aryl fluorides are accessible from daizonium compounds
via the Schiemann Reaction (H. Suschitzky Adv. Fluorine Chem. 1965
4:1-30). The Schiemann reaction is carried out by treating a
diazonium salt, formed by standard protocols, with NaBF.sub.4,
HBF.sub.4 or NH.sub.4BF.sub.4 to form a diazonium tetrafluoroborate
salt which can be isolated and thermally converted to the desired
aryl fluoride while releasing nitrogen and BF.sub.3. Other fluoride
salts such as PF.sub.6.sup.-, SbF.sub.6.sup.- and AsF.sub.6.sup.-
also can be used. Aryl chlorides and bromides are also accessible
through the corresponding tetrachloroborate and tetrabromoborate
salts (G. Olah and W. S. Tolgyesi J. Org. Chem. 1961 26:2053). Aryl
iodides are prepared by treating the diazonium salt with
iodine.
[0049] In another embodiment of the present invention there is
provided a process for the preparation of a compound according to
formula VII which process comprises the steps of (i) contacting an
alkali metal (hetero)aryloxide II with 2,3,4-trifluoronitrobenzene
in a first solvent at temperatures from about -30.degree. C. up to
about 40.degree. C. to afford a
3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III; (ii)
contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound
III with alkali metal salt of an acetic acid ester IV wherein
R.sup.5 is CO.sub.2R.sup.5a or C and R.sup.5a is independently in
each incidence straight or branched C.sub.1-6 alkyl, in a second
solvent with a base at a temperature of at least about -70.degree.
C. up to about 40.degree. C. to afford a
2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono-
or di- and contacting the resulting mono- or di-acid with acid to
afford VI and (iv) contacting VI with a reducing agent to afford
amine VII, wherein R.sup.5 is CO.sub.2R.sup.4a or C and R.sup.4a or
R.sup.4c is hydrogen or C.sub.1-6 alkyl; and, R.sup.1, R.sup.2 and
R.sup.4b are as in claim 1.
[0050] In another embodiment of the present invention there is
provided a process for the preparation of a compound according to
formula VIII (X=Cl or Br) which process comprises the steps of (i)
contacting an alkali metal (hetero)aryloxide II with
2,3,4-trifluoronitrobenzene in a first solvent at temperatures from
about -30.degree. C. up to about 40.degree. C. to afford a
3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III; (ii)
contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound
III with alkali metal salt of an acetic acid ester IV wherein
R.sup.5 is CO.sub.2R.sup.5a or C and R.sup.5a is independently in
each incidence straight or branched C.sub.1-6 alkyl, in an aprotic
solvent with a base at a temperature 10
[0051] of at least about -70.degree. C. up to about 40.degree. C.
to afford a 2-fluoro-3-phenoxyphenylacetic ester V; (iii)
hydrolyzing the mono- or di-ester and contacting the resulting
mono- or di-acid with acid to afford VI; (iv) contacting VI with a
reducing agent to afford amine VII; and (v) contacting the amine
VII with a diazotizing agent and subsequently contacting the
resulting diazonium salt with a cuprous halide to afford VIII,
wherein X is chloro or bromo, R.sup.5 is CO.sub.2R.sup.4a or C and
R.sup.4a or R.sup.4c is hydrogen or C.sub.1-6 alkyl and R.sup.1,
R.sup.2 and R.sup.4b are as defined in claim 1. 11
[0052] In another embodiment of the present invention there is
provided a process for the preparation of a compound according to
formula VIII (X=F) which process comprises the steps of (i)
contacting an alkali metal (hetero)aryloxide II with
2,3,4-trifluoronitrobenzene in a first solvent at temperatures from
about -30.degree. C. up to about 40.degree. C. to afford a
3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III; (ii)
contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound
III with alkali metal salt of an acetic acid ester IV wherein
R.sup.5 is CO.sub.2R.sup.5a or C and R.sup.5a is independently in
each occurence straight or branched C.sub.1-6 alkyl, in an aprotic
solvent with a base at a temperature of at least about -70.degree.
C. up to about 40.degree. C. to afford a
2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono-
or di-ester and contacting the resulting mono- or di-acid with acid
to afford VI; (iv) contacting VI with a reducing agent to afford
amine VII; and (v) contacting the amine VII with a diazotizing
agent in the presence of a tetrafluoroborate salt or
tetrafluoroboric acid and heating said diazonium tetrafluoroborate
to afford VIII where X is fluorine, R.sup.5 is CO.sub.2R.sup.4a or
C and R.sup.4a or R.sup.4c is hydrogen or C.sub.1-6 alkyl and
R.sup.1, R.sup.2 and R.sup.4b are as defined in claim 1.
[0053] In another embodiment of the present invention there is
provided a process for the preparation of a compound according to
formula VIII (X=alkyl) which process comprises the steps of (i)
contacting an alkali metal (hetero)aryloxide II with
2,3,4-trifluoronitrobenzene in a first solvent at temperatures from
about -30.degree. C. up to about 40.degree. C. to afford a
3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III; (ii)
contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound
III with alkali metal salt of an acetic acid ester IV wherein
R.sup.5 is CO.sub.2R.sup.5a or C and R.sup.5a is independently in
each occurence straight or branched C.sub.1-6 alkyl, in an aprotic
solvent with a base at a temperature of at least about -70.degree.
C. up to about 40.degree. C. to afford a
2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono-
or di-ester and contacting the resulting mono- or di-acid with acid
to afford VI; (iv) contacting VI with a reducing agent to afford
amine VII; and (v) contacting the amine VII with a diazotizing
agent and contacting the diazonium salt with CuBr to afford VIII
wherein X is a Br, and (vi) contacting the aryl bromide with a
dialkyl zinc Pd(dppf)Cl.sub.2 and DIBAL to afford VIII (X=alkyl),
wherein R.sup.5 is CO.sub.2R.sup.4a or C and R.sup.4a or R.sup.4c
is hydrogen or C.sub.1-6 alkyl and R.sup.1, R.sup.2 and R.sup.4b
are as defined in claim 1.
[0054] In another embodiment of the present invention there is
provided a compound according to formula III wherein R.sup.2 is as
defined in claim 1.
[0055] In another embodiment of the present invention there is
provided a compound according to formula V wherein R.sup.2,
R.sup.4a, R.sup.4c and R.sup.5 are as defined in claim 1.
[0056] In another embodiment of the present invention there is
provided a compound according to formula X.
[0057] The pyridazinone 10 was obtained utilizing the Wittig
reaction. (see J. W. Schulenberger and S. Archer, Organic
Reactions, Wiley & Sons, New York 1965 vol. 14, chapter 1, pp.
1-51; J. March, Advanced Organic Chemistry, 4.sup.th ed., John
Wiley & Sons, New York, 1992, pp. 956-963). The phosphorane 16
was condensed with citraconic anhydride 17 which produced an
isomeric mixture alkylidene lactones from which the major isomer 18
could be isolated by crystallization (Massy-Westropp, R. A. and
Price, M. F., Aust. J. Chem. 1980, 33, 333-341). Treating 18 with
hydrazine afforded
(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl
ester (10). The present invention thus provides a convergent
synthesis in which separation of the regioisomers is possible on an
easily accessible intermediate early in the synthetic sequence.
12
[0058] The following examples (infra) are given to enable those
skilled in the art to more clearly understand and to practice the
present invention. They should not be considered as limiting the
scope of the invention, but merely as being illustrative and
representative thereof.
EXAMPLE 1
5-[6-Chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-p-
henoxy]-isophthalonitrile (26)
[0059] 13
[0060] A 22 L round-bottom flask was charged with
3,5-bis-tert-butylcarbam- oyl-phenol (20, 360 g, 1.23 mol) and THF
(12.5 L). The resulting slurry was cooled to 0.degree. C. and
potassium tert-butoxide (1.35 L, 1.0 M in THF, 1.35 mol) was added
dropwise over approximately 30 min. After the addition was
complete, the reaction mixture was cooled to between -30 and
-35.degree. C. and 2,3,4-trifluoronitrobenzene (239, 1.35 mol) was
added dropwise over approximately 5 min. The reaction mixture was
stirred at approximately -30.degree. C. for 1 h whereupon the
cooling bath was removed. The reaction mixture was then stirred for
20 h with warming to ambient temperature. A mixture of water (2.0
L) and brine (1.0 L) was added, and the reaction mixture was
stirred vigorously in a 20 L extractor ball. Following removal of
the aqueous phase, the organic layer was washed with additional
brine (1.5 L), and the resulting THF solution was transferred to a
22 L round bottom flask for distillation. The extractor ball was
rinsed with THF (500 mL). After approximately 10 L of THF had been
removed by distillation, addition of isopropyl alcohol (11 L) was
initiated and the distillation was continued until approximately 23
L of distillate had been collected. When the residual volume was 5
L and the pot temperature was 82.degree. C., water (2.0 L) was
added dropwise. Heating was then discontinued, and the reaction
mixture was stirred overnight with cooling to room temperature. The
resulting solid was filtered through a 3 L course-flit sintered
glass filter funnel. The filter cake was washed with IPA/H.sub.2O
(1:1, 2.times.600 mL) and dried in a vacuum oven (70.degree. C., 25
Torr) to afford
N,N'-di-tert-butyl-5-(2,3-difluoro-6-nitro-phenoxy)-isophthalamide
(21; 488 g, 88% theory). 14
[0061] A 5 L round bottom flask was charged with
N,N'-di-tert-butyl-5-(2,3-
-difluoro-6-nitro-phenoxy)-isophthalamide (21; 564 g) and 1.3 L of
phosphorus oxychloride. The mixture was heated to between
90.degree. C. and 100.degree. C. for 2 h after which approximately
{fraction (1/2)} of the POCl.sub.3 was removed by distillation.
Toluene was added (1 L) and additional liquid was distilled.
Cooling the mixture overnight and filtering the solid gave crude
product. Additional material was obtained by further concentration,
treatment with water (2 L) and filtration of the resulting
material. The combined solids were stirred in MeOH (0.7 L) for
between 1 and 3 h, filtered and dried in a vacuum oven between
50.degree. C. and 80.degree. C. at 25 Torr with a nitrogen bleed to
afford 339 g of 22 (90% theory). 15
[0062] A 5 L three-neck round bottom flask was charged with
(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-3-yl)-acetic acid
tert-butyl ester (10; 223 g, 0.996 mol) and THF (700 mL). The
resulting solution was cooled to 0.degree. C. and potassium
tert-butoxide (1.2 L, 1.66 M in THF, 1.99 mol) was added dropwise
over approximately 30 min. After cooling the reaction mixture to
-55.degree. C., a solution of 5-(2,3-difluoro-6-nitro-
-phenoxy)-isophthalonitrile (22; 150 g; 0.498 mol) in THF (1.0 L)
was added dropwise over approximately 1 h. Following a THF rinse
(500 mL), the cooling bath was removed, and the reaction mixture
was stirred for 19 h with warming to ambient temperature. The
reaction mixture was then quenched by the addition of 1N HCl (1.75
L). Following removal of the aqueous layer (2 L, pH of 34) the
organic phase was washed with water (1.0 L) and brine (750 mL). The
resulting THF solution was filtered through CELITE.RTM. and the
filter aid washed with THF (500 mL). The solution was then
concentrated in vacuo to afford a dark oil which was dissolved in
NMP (850 mL) and warmed to approximately 50.degree. C. Water (425
mL) was added dropwise. The cloudy solution was stirred slowly,
seeded with a crystal and cooled to 0.degree. C. After stirring at
0.degree. C. for 30 min, the product was filtered. The filter cake
was then washed with MeOH (100 mL, 200 mL) and dried in a vacuum
oven (50.degree. C., 25 Torr) to afford
[3-(3,5-dicyano-phenoxy)-2-fluoro-4-ni-
tro-phenyl]-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid
tert-butyl ester (23; 157 g, 62% theory). 16
[0063] A slurry of 23 (771.1 g), methanesulfonic acid (100 mL) and
acetonitrile (1.5 L) was heated to 70.degree. C. under a N.sub.2
atmosphere for 2 h. The solution became homogenous at approximately
52.degree. C. and a solid precipitate reformed after 30 min at
70.degree. C. The reaction mixture was diluted with water (3084 mL)
and IPA (3084 mL) and the resulting mixture was aged at 63.degree.
C. for 1 h. The heating was stopped and the resulting solution
allowed to slowly cool to RT. The solid product was recovered by
filtration and the resulting filter cake was thrice washed with
H.sub.2O:MeOH (1:1, 500 mL) and dried overnight in a vacuum oven at
80.degree. C. which afforded 24 (603.5 g, 97.6% theory). 17
[0064] A suspension of
5-[2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-
-3-ylmethyl)-6-nitro-phenoxy]-isophthalonitrile (24; 200 g, 0.494
mol) in THF (3.2 L) was warmed to 66.degree. C. to dissolve the
solid and the solution was cooled to RT. To resulting solution was
added VO(acac).sub.2 (6.542 g, 24.7 mmol) and 5% palladium
(sulfided) on carbon (JM Catalyst # 11; 10.0 g) and the resulting
suspension was stirred overnight at RT under a hydrogen atmosphere.
The resulting suspension was filtered and the solvent was removed
in a rotary evaporator (approximately 2.7 L), a solid precipitate
formed and IPA (2.0 L) was added. An additional 600 mL of solvent
was removed by evaporation after which the suspension was aged at
40.degree. C. for 5 h and then cooled to RT. The solid was filtered
and washed thrice with H.sub.2O:IPA (1:1 v/v, approximately 700
mL). The filtrate and washes were combined and concentrated to
afford an additional 23.3 g of product. There was obtained 375.4 g
(98% theory) of
5-[6-amino-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-p-
henoxy]-isophthalonitrile (25). 18
[0065] A suspension of 25 (156 g, 0.416 mol) and THF (3.7 L) was
heated to reflux to dissolve the amine and approximately 2.3 L of
THF was distilled from the solution. A solution of BF.sub.3
etherate (78.3 mL, 88.48 g, 0.623 mol) and 200 mL of THF was cooled
to -15.degree. C. The amine solution was pumped into the cooled
solution approximately 10 min. The reaction mixture was then
maintained at -15.degree. C. for 15 minutes. A solution of
tert-butyl nitrite (51.43 g, 0.499 mol) and THF (50 mL) was added
over a 5 min period. The cooling bath was removed and the mixture
allowed to warm. After 2.5 h the reaction was quenched by the
addition of 2.25 L hexane and the resulting solid was stirred and
finally filtered. The solid was washed with hexane (4.times.500 mL)
and the resulting solid was dried in a vacuum oven overnight at
30.degree. C. to afford 198 g of the diazonium tetrafluoroborate
salt.
[0066] CuCl was suspended in MeCN (600 mL) and heated to 65.degree.
C. A suspension of the crude diazonium tetrafluoroborate in MeCN
(900 mL) was pumped into the cuprous chloride solution over a 10
min period. The pump was washed with MeCN (350 mL). After 1 h at
65.degree. C. the reaction mixture was cooled to about 40.degree.
C. and 3M HCl (2.0 L) was added, after which cyclohexane (2.0 L)
was added and stirred for 15 min. The resulting precipitate was
filtered and washed with water (250 mL) and EtOH (2.times.400 mL)
to afford a light yellow solid which was dried in a vacuum oven at
55.degree. C. to afford 26 (131.6 g, 84.9% theory). An additional
16 g of product was obtained by extracting the aqueous phase with
twice with DCM (2.0 L), evaporating the organic phase and
chromatographing the resulting oil on silica gel.
[0067]
3-Chloro-5-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridaz-
in-3-ylmethyl)-phenoxy]-benzonitrile and
3-[6-chloro-2-fluoro-3-(5-methyl--
6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-5-fluoro-benzonitrile
was prepared by an analogous procedure except
3-chloro-5-cyanophenol and 3-cyano-5-fluorophenol respectively were
substituted for 20 and the POCl.sub.3 dehydration (step 2) was
omitted.
EXAMPLE 2
(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl
ester (10)
[0068] 19
[0069] To a cooled (12.degree. C.) solution of the phosphorane (16;
3.008 Kg; 7.99 mol) in THF (12 L) was added citraconic anhydride
(1.35 Kg; 12.04 mol) over a 4 h period during which the temperature
rose to 35 C. Following the addition, approximately 10 L of THF was
removed by distillation and replaced with 4 L of methanol. Addition
liquid was removed by distillation and replaced by methanol. A
total of 14.6 L was distilled and 7 L of methanol added. To the
mixture was added 1 L of water and 6 L of cyclohexane. The
cyclohexane layer was separated, and the lower (methanol-water)
layer was repeatedly extracted with cyclohexane (a total of 12
extractions each with approximately 6 L of cyclohexane). The
cyclohexane fractions were combined and concentrated on a rotary
evaporator. After solvent removal, methanol (1 L) was added and the
mixture further concentrated on a rotary evaporator. The resulting
oil was taken up in methanol (2 L) and cooled to -12.degree. C. for
3 h. After filtration, the solid cake was washed with MeOH (400 mL
cooled to 0.degree. C.) and the solid was dried in a vacuum
desiccator to afford (4-ethyl-5-oxo-5H-furan-2-ylidene)-acetic acid
tert-butyl ester (18, 950 g; 56.6% yield).
[0070] To a solution of lactone 18 (2.68 Kg; 12.77 mol) in 7.5 L of
NMP cooled to below 0.degree. C. was added 420 mL of anhydrous
hydrazine (equivalent quantities of hydrazine hydrate also can be
used) while maintaining the internal temperature at less than
20.degree. C. After the addition was completed the reaction mixture
was heated to 110-145.degree. C. for one to five h. The reaction
mixture was cooled and diluted with H.sub.2O (11 L) which resulted
in the formation of crystalline pyridazinone 10 which was filtered
and washed with water (2.times.2 L) and dried to afford 2.23 Kg
(77.9%) of product.
EXAMPLE 3
6-[4-Chloro-2-fluoro-3-(1H-indol-7-yloxy)-benzyl]-4-methyl-2H-pyridazin-3--
one (31)
[0071] 20
[0072] Solid sodium tert-butoxide was added to a ice cold solution
of 7-hydroxyindole (1.23 g, 9.24 mmol; Synthetic Communications
2003 33:507) in anhydrous THF (145 mL) under a nitrogen atmosphere.
The mixture was stirred for 10 min, and 2,3,4-trifluoronitrobenzene
(1.06 mL, 9.24 mmol) was added dropwise. The brown solution was
stirred for 2 h, and then added to a saturated aqueous solution of
NH.sub.4Cl (150 mL). The aqueous layer was extracted with EtOAc
(3.times.100 mL), and the combined organic fractions were washed
with H.sub.2O (100 mL), brine (75 mL), and dried over anhydrous
MgSO.sub.4. The solvents were evaporated, and the remaining oil was
purified by flash chromatography on silica gel (0% to 30%
EtOAc/hexanes) to afford 2.26 g (84%) of 27. 21
[0073] Phenyl sulfonyl chloride (1.05 mL, 8.18 mmol), powdered NaOH
(4 g), and Bu.sub.4NHSO.sub.4 (400 mg) were added sequentially to a
solution of 27 (2.26 g, 7.79 mmol) in anhydrous CH.sub.2Cl.sub.2
(25 mL). The mixture was stirred for 3 h, and then filtered through
CELITE.RTM.. The filtrate was washed with H.sub.2O (25 mL), and
dried over anhydrous MgSO.sub.4. The solvents were evaporated, and
the remaining material was recrystallized from EtOAc. The impure
filtrate was purified by column chromatography on silica gel (25%
to 40% EtOAc/hexanes), and combined with the crystallized material
to afford 2.08 g (62%) of 28. 22
[0074] A solution of sodium hexamethyldisilazane (15.5 mL of a 1 M
solution in THF, 15.5 mmol) was added slowly to a solution of 28
(2.08 g, 4.83 mmol) and 10 (1.14 g, 5.07 mmol) in anhydrous THF (25
mL) under nitrogen at 0.degree. C. The reaction mixture was stirred
for 3 h, and then added to a saturated aqueous solution of
NH.sub.4Cl (200 mL). The aqueous mixture was extracted with EtOAc
(3.times.70 mL). The combined organic fractions were then washed
with brine (50 mL), and dried over anhydrous MgSO.sub.4.
Evaporation of the solvents afforded a red oil which was dissolved
in acetic acid (100 mL) and heated to reflux for 5 h. The solvent
was removed, and the remaining material was dissolved in EtOAc (100
mL). The organic layer was washed with H.sub.2O (40 mL), brine (25
mL), and dried over anhydrous MgSO.sub.4. The solvents were
evaporated and the crude product purified by flash chromatography
on silica gel (20% to 100% EtOAc/hexanes) to afford 29 (1.79 g,
69%) as a solid that was only slightly soluble in EtOAc. 23
[0075] A mixture of pyridazinone 29 (1.79 g, 3.36 mmol), Fe powder
(845 mg, 15.12 mmol), and NH.sub.4Cl (809 mg, 15.12 mmol) in EtOH
(60 mL) and H.sub.2O (15 mL) was heated to reflux for 3 h. The
reaction mixture was cooled to RT and filtered through CELITE.RTM..
The filter cake was washed with EtOAc (150 mL), and the combined
organic fractions were washed with brine (75 mL), and dried over
anhydrous MgSO.sub.4. The solvents were evaporated to provide an
oil. The oil was dissolved in CH.sub.2Cl.sub.2 (100 mL), and the
organic layer was washed with brine (50 mL), and dried over
anhydrous MgSO.sub.4. Evaporation of the solvent provided 30 (1.50
g; 88% theory). 24
[0076] The aniline 30 (700 mg, 1.39 mmol) and CuCl.sub.2 (381 mg,
2.77 mmol) were suspended in anhydrous CH.sub.3CN (14 mL) under a
nitrogen atmosphere. tert-Butylnitrite (0.33 mL, 2.77 mmol) was
added dropwise, and the reaction mixture was warmed to 60.degree.
C. for 1 h. The solution was cooled to RT, and a 5% aqueous HCl
solution (20 mL) was added. The layers were separated, and the
aqueous layer was extracted with EtOAc (3.times.30 mL). The
combined organic fractions were washed with brine (30 mL) and dried
over anhydrous MgSO.sub.4. The solvents were evaporated, and the
remaining solid was purified by flash chromatography over silica
gel (20% to 100% EtOAc/Hexanes) to provide 500 mg of a solid. The
solid was dissolved in anhydrous THF (10 mL) under nitrogen, and
TBAF was added dropwise (5.73 mL of a 1.0 M solution, 5.73 mmol).
The solution was heated to reflux for 1 h and then cooled to RT.
The mixture was quenched with saturated aqueous NaHCO.sub.3, and
the aqueous solution was extracted with CH.sub.2Cl.sub.2
(3.times.30 mL). The combined organic fractions were washed with
H.sub.2O (30 mL), brine (30 mL), and dried over anhydrous
MgSO.sub.4. The solvents were evaporated, and the remaining solid
was purified by repeated flash chromatography on silica gel (1% to
3% MeOH/CH.sub.2Cl.sub.2) to afford 31 (135 mg; 25% theory).
EXAMPLE 4
6-[3-(5-bromo-1-oxy-pyridin-3-yloxy).sub.4-chloro-2-fluoro-benzyl]4-methyl-
-2H-pyridazin-3-one (41)
[0077] 25
[0078] A solution of 3,5-dibromopyridine (32, 20 g, 84.4 mmol) in
DMF (200 mL) was stirred at RT under nitrogen atmosphere and 21.3
mL of sodium methoxide (25% by wt. in methanol, 92.8 mmol) was
added slowly. The reaction mixture was stirred overnight at
70.degree. C. under N.sub.2. The reaction was cooled to RT and
quenched with water (200 mL) and extracted with Et.sub.2O
(2.times.200 mL). The combined organic extracts was washed with
brine, dried (MgSO.sub.4) and concentrated in vacuo. The crude
3-bromo-5-methoxypyridine (33, 14.8 g, 93% theory) afforded a
colorless oil after flash chromatography on silica gel
(EtOAc:hexane 1:10). 26
[0079] A solution of 3-bromo-5-methoxy-pyridine (33 18.8 g, 0.1
mol), HBr (80 mL, 48%) and glacial HOAc (60 mL) was stirred
overnight at 120.degree. C. Hydrobromic acid (60 mL, 48%) was added
slowly to replace evaporated solvents and stirred at 120.degree. C.
for overnight. The reaction mixture was cooled to RT and then
poured into the ice. The pH was adjusted to about 6 by adding 6N
NaOH and then extracted with EtOAc (2.times.200 mL). The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The crude product was stirred in CH.sub.2Cl.sub.2 (150 mL) and the
resulting precipitate was filtered. The product was washed with
CH.sub.2Cl.sub.2 to afford 3-bromo-5-hydoxypyridine (34; 15.2 g,
87.4% theory) as a white solid. 27
[0080] A solution of 3-bromo-5-hydoxypyridine (34, 7.4 g, 42.5
mmol) in anhydrous THF (40 mL) was stirred at 0.degree. C. under Ar
atmosphere and potassium tert-butoxide (46.8 mL, 1M solution in
THF) was added slowly. After 1 h at 0.degree. C.,
2,3,4-trifluoronitrobenzene (7.91 g, 44.6 mmol) in 15 mL of THF was
added very slowly. The reaction mixture was stirred at RT for 2 h,
quenched with water (80 mL) and extracted with EtOAc (2.times.80
mL). The combined organic extracts were dried (MgSO.sub.4) and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (EtOAc:hexane 1:15) to afford 35 (11
g, 78%) as a light orange oil. 28
[0081] A solution of
(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl
ester (10, 7.1 g, 31.7 mmol) and 35 (11 g, 33.3 mmol) in anhydrous
THF (30 mL) was stirred at -78.degree. C. under an Ar atmosphere
and 112 mL of LiHMDS (1.0M solution in THF) was added very slowly.
The reaction mixture was stirred in the cold bath (dry-ice/IPA) for
3 h then in an ice bath for 2 h. The reaction was quenched with a
solution of NaHSO.sub.4.H.sub.2O (5% by wt) and extracted with
EtOAc (2.times.100 mL). The combined organic extracts were dried
(MgSO.sub.4) and concentrated in vacuo. The product was isolated by
a flash chromatography on silica gel (EtOAc:hexane 1:2 to 2:1) to
afford 36 as a yellow solid (10.2 g, 60% yield). 29
[0082] A solution of 36 (10.2 g, 19.1 mmol) in HOAc (120 mL) under
a nitrogen atmosphere was heated to reflux overnight. It was cooled
to RT and the HOAc was evaporated in vacuo. A saturated NaHCO.sub.3
solution (70 mL) was added and the aqueous mixture extracted with
EtOAc (2.times.80 mL). The combined organic fractions were dried
(MgSO.sub.4) and concentrated in vacuo. The crude product was
isolated by a flash chromatography. on silica gel (EtOAc:hexane 1:2
to 2:1) to afford 37 as a light yellow solid (4.6 g, 55.3% theory):
ms (M+H).sup.+=436. 30
[0083] A solution of 37 (1.8 g, 4.4 mmol), di-tert-butyl
dicarbonate (1.16 g, 5.3 mmol), and 4-dimethylaminopyridine (0.2 g)
in anhydrous THF (30 mL) was maintained under an Ar atmosphere and
stirred at RT overnight. The reaction mixture was quenched with
water and extracted with EtOAc (2.times.30 mL). The combined
organic fractions were dried (MgSO.sub.4) and concentrated in
vacuo. The product was isolated by a flash chromatography on silica
gel (1:10 to 2:1 EtOAc:hexane) to afford 38 as a white solid
compound (0.85 g; 38% theory). 31
[0084] To a solution of 38 (4 g; 9.19 mmol) in absolute EtOH (60
mL) was added NH.sub.4Cl (0.984 g, 18.40 mmol) dissolved in water
(10 mL). The resulting mixture was heated at 60.degree. C. until
the reaction was homogeneous. Fe(0) (0.77 g, 13.78 mmol) was then
added and the mixture stirred vigorously at 60.degree. C. for 6 h.
When reduction was complete the hot reaction mixture was filtered
through a pad of CELITE.RTM. which subsequently was washed with hot
EtOAc. The resulting filtrated was cooled and extracted with EtOAc
and the combined extracts washed sequentially with water and brine.
The EtOAc extract was dried (Na.sub.2SO.sub.4), filtered and the
volatile solvent was removed in vacuo to afford a pale orange oil
which was recrystallized from hexanes to yield 39 (1.8 g, 48.3%
theory). 32
[0085] Aniline 39 (0.85 g, 1.69 mmol) and CuCl.sub.2 (575 mg, 3.37
mmol) were suspended in anhydrous CH.sub.3CN (20 mL) under a
nitrogen atmosphere. tert-Butyl nitrite (0.348 g, 3.37 mmol) was
added dropwise, and the reaction mixture was warmed to 60.degree.
C. for 1 h. The solution was cooled to RT, and a 5% aqueous HCl
solution (20 mL) was added. The layers were separated, and the
aqueous layer was extracted with EtOAc (3.times.30 mL). The
combined organic fractions were washed with brine (30 mL) and dried
over anhydrous MgSO.sub.4. The solvents were evaporated, and the
remaining solid was purified by flash chromatography over silica
gel (20% to 100% EtOAc/hexanes) to provide 500 mg of a solid. The
solid was dissolved in anhydrous DME (10 mL) and TFA (1 mL) was
added. The solution was stirred at RT for 1 h. The mixture was
quenched with saturated aqueous NaHCO.sub.3, and the aqueous
solution was extracted with CH.sub.2Cl.sub.2 (3.times.30 mL). The
combined organic fractions were washed with H.sub.2O (30 mL), brine
(30 mL), and dried over anhydrous MgSO.sub.4. The solvents were
evaporated, and the remaining solid was purified by repeated flash
chromatography on silica gel (1% to 3% MeOH/CH.sub.2Cl.sub.2) to
afford 40 (290 mg; 49.9% theory; mp 184.9-188.degree. C., ms
[M+H]+=424). 33
[0086] A solution of the pyridine 40 (0.2 g, 0.47 mmol) and MCPBA
(0.09 g, 0.52 mmol) in anhydrous chloroform (10 mL) was heated at
reflux for 6 hours. The reaction mixture was cooled to RT, and
diluted with 0.05N NaOH (5 mL) and extracted with chloroform
(2.times.10 mL). The combined organic fractions were dried
(MgSO.sub.4) and concentrated in vacuo. The crude product was
purified by a flash chromatography on silica gel
(MeOH:CH.sub.2Cl.sub.2 0.1 to 1:10) to afford
6-[3-(5-bromo-1-oxy-pyridin-
-3-yloxy)-4-chloro-2-fluoro-benzyl]-4-methyl-2H-pyridazin-3-one
(41, 60 mg; 32% theory) as a white solid: mp 197.9-198.9.degree.
C., ms (M+H).sup.+=440.
EXAMPLE 5
[0087] 34
[0088] To a 250 mL round bottom flask charged with
3,5-dichlorobenzonitril- e (42; 7.31 g; 34.90 mmol) and maintained
under an argon atmosphere was added DMF (70 mL). The flask was
cooled to 0.degree. C. and powdered sodium methoxide (1.88 g; 34.90
mmol) was added in two portions 15 min apart. The homogeneous
mixture was allowed to warm to room temperature and stirred for 24
h. The solution was cooled to 0.degree. C. and aqueous 10% HCl (20
mL) was added dropwise via an addition funnel after which the
reaction was warmed to RT. The mixture was extracted with EtOAc and
the combined extracts washed sequentially with water and brine. The
organic phase was dried (Na.sub.2SO.sub.4), filtered, and volatile
solvents were removed in vacuo. The resulting solid was
recrystallized from hexanes to afford
3-chloro-5-methoxybenzonitrile (43, 4.2 g; 72%).
[0089] A 250 mL round bottom flask was charged with 43 (4.2 g;
25.05 mmol) and 2,4,6-collidine (60 mL) was added. The mixture was
stirred under an argon atmosphere until the solution was
homogeneous. Anhydrous lithium iodide (10.06 g; 75.18 mmol) was
added and the mixture was heated to 175.degree. C. for 3 h. The
reaction mixture was cooled to RT and partitioned between 10% HCl
and EtOAc. The EtOAc phase was washed sequentially with 10% HCl and
brine, dried (Na.sub.2SO.sub.4), filtered and evaporated in vacuo
to afford a oil which was crystallized from hexanes to afford
3-chloro-5-hydroxybenzonitrile (44, 3.5 g, 91% theory). 35
[0090] To an ice-cold solution of 3-chloro-5-hydroxybenzonitrile
(44; 3.5 g; 22.80 mmol) and dry THF (50 mL) maintained under an
argon atmosphere was added sodium tert-butoxide (2.2 g; 22.80 mmol)
in two portions 15 min apart. The reaction mixture was stirred
until the mixture was homogeneous. To the ice-cold solution was
added dropwise 2,3,4-trifluoronitrobenzene (4.0 g; 22.80 mmol) over
30 min. The reaction was stirred at 0.degree. C. for 3 h and then
allowed to warm to RT. The reaction was cooled to 0.degree. C. and
quenched by addition of 10% HCl via addition funnel. The resulting
mixture was extracted with EtOAc and the combined organic phases
washed sequentially with 10% HCl and brine. The EtOAc was dried
(Na.sub.2SO.sub.4), filtered and the volatile solvent removed in
vacuo to yield a yellow oil which was crystallized from hexanes to
yield 45 (6.3 g, 89% theory) 36
[0091] To an ice-cold solution of tert-butyl ethyl malonate (3.8 g;
20.28 mmol) and dry NMP maintained under an argon atmosphere was
added NaH (1.2 g, 48.67 mmol, 60% in mineral oil) over a 45 min
interval. The reaction was stirred for an additional 30 min after
which 45 (6.3 g, 20.28 mmol) was added dropwise and the resulting
solution stirred for 4 h. The reaction mixture was cooled to
0.degree. C. and quenched by dropwise addition of a saturated
NaHSO.sub.4 solution. The mixture was extracted with EtOAc and the
combined organic extracts washed sequentially with water and brine.
The EtOAc solution was dried (Na.sub.2SO.sub.4), filtered and the
volatile solvents removed in vacuo to afford 46 as a purple oil
that was used without further purification. 37
[0092] The crude mixed ester 46 from the previous step (8.9 g;
18.60 mmol) was dissolved in DCM (100 mL) and 50 mL of TFA was
added and the solution was to heated to 60.degree. C. for 24 h. The
reaction mixture was cooled to 0.degree. C. and saturated
NaHCO.sub.3 was added dropwise to the stirred reaction mixture. The
resulting solution was extracted with EtOAc and washed sequentially
with saturated NaHCO.sub.3, water and brine. The organic phase was
dried (Na.sub.2SO.sub.4), filter and the volatile solvents removed
in vacuo. The resulting dark oil was crystallized from hexanes to
afford 47 (6.5 g, 92% theory). 38
[0093] To a solution of 47 (6.5 g; 17.20 mmol) and absolute EtOH
(100 mL) was added NH.sub.4Cl (1.84 g, 34.39 mmol) dissolved in
water (20 mL). The resulting mixture was heated at 60.degree. C.
until the reaction was homogeneous. Fe(0) (1.44 g, 25.80 mmol) was
then added and the mixture stirred vigorously at 60.degree. C. for
6 h. When reduction was complete the hot reaction mixture was
filtered through a pad of CELITE.RTM. which subsequently was washed
with hot EtOAc. The resulting filtrate was cooled and extracted
with EtOAc and the combined extracts washed sequentially with water
and brine. The EtOAc extract was dried (Na.sub.2SO.sub.4), filtered
and the volatile solvent was removed in vacuo to afford a pale
orange oil which was crystallized from hexanes to yield 48 (5.0 g,
83% theory).
[0094] Introduction of 5-Bromo Substituent 39
[0095] A 150 mL three-neck round bottom flask was charged with MeCN
(50 mL), CuBr (2.8 g, 12.61 mmol) and t-butyl nitrite (1.4 g, 13.76
mmol), degassed and maintained under an Ar atmosphere and heated to
70.degree. C. To the mixture was added dropwise a solution of 48
(4.0 g, 11.47 mmol) dissolved MeCN (20 mL). The reaction mixture
was stirred at 70.degree. C. for 4 h and then cooled to 0.degree.
C. The reaction was quenched by addition of 10% HCl (30 mL) and
extracted with EtOAc. The combined extracts were sequentially
washed with 10% HCl and brine. The organic extract was dried
(Na.sub.2SO.sub.4), filtered and the volatile solvents removed in
vacuo to yield a black oil which was purified by flash
chromatography on silica gel (hexanes:EtOAc 95:5) to afford 49 (2.5
g, 52.8% theory).
[0096] Introduction of 5-Methyl Substituent 40
[0097] To a degassed ice-cold solution of THF (15 mL),
Pd(dppf)Cl.sub.2 (0.09 g, 0.121 mmol) was added DIBAL-H (0.012
mmol; 1M in toluene). The reaction mixture was allowed to warm to
RT. A solution of 49 (1.0 g, 2.42 mmol) was added followed by
dimethyl zinc (1M in THF, 4.240 mmol). The reaction was heated to
65.degree. C. for 4 h, cooled to RT and quenched with aqueous
NH.sub.4Cl. The resulting mixture was extracted with EtOAc and
washed sequentially with NH.sub.4Cl and brine. The EtOAc extract
was dried (Na.sub.2SO.sub.4), filtered and the volatile solvent
removed in vacuo to yield a dark brown oil that was purified by
flash chromatography on silica gel (hexanes:EtOAc 95:5) to yield 50
(0.50 g, 59% theory).
[0098] Introduction of 5-Ethyl Substituent 41
[0099] 51 was prepared in by an identical procedure to 50 except
diethylzinc was substituted for dimethyl zinc. The product was
purified by flash chromatography on silica gel (hexanes:EtOAc 95:5)
to yield 49 (0.65 g, 74% theory).
[0100] Introduction of a pyridazinone into 49, 50 or 51 is carried
out by the deprotonation of the phenylacetic acid and condensation
with 3,6-dichloropyrazine as described in U.S. Ser. No. 10/807,993
(J. P. Dunn et al., U.S. Publication 20040198736.).
[0101]
[4-Chloro-3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-phenyl]-ace-
tic acid ethyl ester,
[4-Bromo-3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluo-
ro-phenyl]-acetic acid ethyl ester,
[3-(3-cyano-5-difluoromethyl-phenoxy)--
2-fluoro-4-methyl-phenyl]-acetic acid ethyl ester and
[3-(3-cyano-5-difluoromethyl-phenoxy)-4-ethyl-2-fluoro-phenyl]-acetic
acid ethyl ester were prepared by a similar route except in step
2,3-chloro, 5-hydroxy benzonitrile was replaced with
3-difluoromethyl-5-hydroxy-benzonitrile. These compounds are useful
synthetic intermediates for the synthesis of pyridazinone
compounds.
[0102] The features disclosed in the foregoing description, or the
following claims expressed in their specific forms or in terms of a
means for performing the disclosed function, or a method or process
for attaining the disclosed result, as appropriate, may,
separately, or in any combination of such features, be utilized for
realizing the invention in diverse forms thereof.
[0103] The foregoing invention has been described in some detail by
way of illustration and example, for purposes of clarity and
understanding. It will be obvious to one of skill in the art that
changes and modifications may be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
[0104] All patents, patent applications and publications cited in
this application are hereby incorporated by reference in their
entirety for all purposes to the same extent as if each individual
patent, patent application or publication were so individually
denoted.
* * * * *